Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder.
Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder.
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DOI：
10.1097/fpc.0000000000000173
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发表时间：
2015-11
影响因子：
2.6
通讯作者：
Cook EH
中科院分区：
文献类型：
--
作者：
Bishop JR;Najjar F;Rubin LH;Guter SJ;Owley T;Mosconi MW;Jacob S;Cook EH
选择性5-羟色胺再摄取抑制剂（如艾司西酞普兰）通常用于治疗自闭症谱系障碍（ASD）患者，但治疗反应和耐受性存在个体差异。CYP 2C 19编码负责艾司西酞普兰代谢的主要酶，我们在ASD的药物遗传学研究中研究了CYP 2C 19的多态性是否与症状和剂量相关。参与者每周完成异常行为检查表-社区版（ABC-CV），持续6周。艾司西酞普兰的起始剂量为2.5 mg qd，每周增加至20 mg，除非发生不可耐受的副作用。检查了三个CYP 2C 19代谢者组（包括超速、快速和减速代谢者）与症状改善和耐受剂量的关系。ABC-CV评分在治疗过程中有所改善（p<0.0001）。代谢者组间ABC-CV-易激惹子量表的改善率无差异，这是临床症状的主要结局。代谢者组存在时间与剂量相互作用的趋势（p=0.10）。这种相互作用是由还原代谢型和超速代谢型组之间从第1周至研究终点的线性变化率驱动的（p=0.05）。事后分析发现，超速代谢者和快代谢者之间以及超速代谢者与慢代谢者之间的剂量递增速率存在显著差异（p <0.04），超速代谢者的剂量随时间变化速率较慢。在该ASD研究样本中，CYP 2C 19超快代谢者与对开放标签艾司西酞普兰固定滴定方案的耐受性降低相关。可能的解释可能涉及更快代谢者的动力学改变或艾司西酞普兰代谢物的先前未知活性。
Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with Autism Spectrum Disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD. Participants completed the Aberrant Behavior Checklist-Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg qd with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose. ABC-CV scores improved over the course of treatment (p<0.0001). There were no differences identified in the rate of improvement across metabolizer groups for the ABC-CV-irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (p=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (p=0.05). Post hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared to reduced metabolizers (p’s<0.04), whereby ultrarapid metabolizers exhibited a slower rate of change in dose over time. CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.